Metabolites of arachidonic acid constitute a class of important biological compounds. Members of this class include prostaglandins, prostacyclins, thromboxanes, and leukotrienes.
The leukotrienes are recent additions to this family of biologically important compounds. The leukotrienes are unsaturated fatty acid compounds derived from arachidonic acid by the action of lipoxygenase. Pioneering work in the isolation and identification of leukotrienes was reported at the Fourth International Prostaglandin Conference in 1979 by Samuelsson, et al., Leukotrienes: A New Group of Biologically Active Compounds, Advances in Prostaglandin and Thromboxane Research, Vol. 6, 1-18, (1980). Early synthetic work in the field was presented at the same conference by Corey, et al., Recent Studies on the Chemical Synthesis of Eicosanoids, Advances in Prostaglandin and Thromboxane Research, Vol. 6, 19-25, (1980). The leukotrienes constitute a general biological control system based on the precursor molecule arachidonic acid. Arachidonic acid is normally stored in biological membrane structures and can be released through activation of a hydrolytic system by a variety of stimuli. Depending on the availability of active enzymes in the stimulated cell, arachidonic acid transforms into one or several biologically active compounds. A variety of stimuli can thus be converted into a multitude of compounds that can regulate or mediate various cell functions. The new knowledge about this system suggests new possibilities for the development of novel and more specific therapeutic agents, particularly in diseases related to immediate hypersensitivity reactions and inflammation. Such drugs might be based on antagonism of end products or inhibition of enzymes involved in the generation and further transformation of key intermediates, Samuelsson, Leukotrienes: Mediators of Immediate Hypersensitivity Reactions and inflammation, Science, Vol. 220, 568-575, (1983).
Continuing work has shown the leukotrienes are important in the cellular regulation of diverse functions. LTB.sub.4, itself, stimulates aggregation and degranulation of human neutrophils, promotes chemotaxis and chemokinesis of leukocytes, mediates lysosomal enzyme release and superoxide generation and constricts respiratory smooth muscle through an indirect mechanism involving stimulation of the release of cycloxygenase products. LTB.sub.4 is implicated in cystic fibrosis, asthma, adult respiratory distress syndrome, cutaneous allergic reactions, spondyloarthritis, rheumatoid arthritis, gout and inflammatory bowel disease because elevated concentrations of LTB.sub.4 have been found in sputum, lung edema fluid, epidermis, skin chamber fluid, synovial fluid and mucosa, Goetzl, et al., Journal of Clinical Immunology, 82, (1984). The known effects of LTB.sub.4 indicate agonists or antagonists would be useful in many physiological conditions. For example, an LTB.sub.4 antagonist would be useful in the treatment of inflammatory conditions where it is desirable to prevent migration of polymorphonuclear leukocytes to the inflammatory site. An LTB.sub.4 antagonist would also be useful in the treatment of respiratory diseases associated with hypersensitivity because the leukotrienes are potent constrictors of human bronchi, Dahlen, Nature, Vol. 288, 484, (1980). As noted, LTB.sub.4 is found in the sputum of cystic fibrosis patients, Cromwell, et al., The Lancet, July 25, 164-165, (1981), suggesting the leukotrienes contribute to the rate of mucous secretions in the human respiratory tract. The excessive production of mucus, however, is a symptom of many pulmonary diseases. For example, in chronic bronchitis the flow of mucus may increase up to four times the normal rate. The inability of the patient to deal with this hyper-production causes conditions such as chronic bronchitis, asthma, and cystic fibrosis.
The role of leukotrienes as agonists in immediate hypersensitivity and other pathological conditions has led to research into inhibitors of leukotriene biosynthesis and leukotriene antagonists, Corey, et al., Tetrahedron Letters, 4243, (1980). Receptors for LTB.sub.4 have been characterized in human neutrophils and HL-60 cells. Although many compounds are known which interfere with the biosynthesis of LTB.sub.4, relatively few agents have been prepared which directly block its pharmacological effects. LTB.sub.4 diacetate has been reported to competitively inhibit chemotactic response of equimolar concentrations of LTB.sub.4. The corresponding dimethylamide of LTB.sub.4 is reported to inhibit neutrophil degranulation induced by LTB.sub.4 at concentrations where the agent has no appreciable agonist activity.